Transplant patients are quite susceptible to opportunistic viral infection resulting from immune suppression necessary for maintenance of their graft. In the case of renal transplant, 17,604 patients in 2011, a new graft means being taken off dialysis, improving quality of life and saving U.S. healthcare nearly $1 B annually. Therefore it is essential that the graft survive. A distinct threat to survival is the cumulative efect of cytomegalovirus (CMV), and polyomavirus (BKV and JCV) infections that directly target the kidney, are immune modifying, and infect concurrently. Diagnosis is difficult as patients are asymptomatic and unable to mount detectable immune responses required for serologic tests; an infection comprising immunomodulatory viruses like CMV, BKV, or JCV amplifies immune suppression medications; thereby the intuitive response to reduce immunosuppression further unbridles infection. Due to the indistinct patient presentation providers are apt to admit patients resulting in average hospital stays of 10.5 days, costing $63,000 for each admission. Existing antiviral treatments target a single virus and carry black box warnings of nephrotoxicity and cytopenia; which further challenge the immune system and kidney. Furthermore, BKV and JCV infections lack therapy, and are managed by reducing immunosuppression, putting the graft organ at risk of rejection. The present project proposes to validate a paradigm-shifting antiviral mechanism-of-action, the activation of host-encoded viral restriction factors, human sirtuins, by a single small molecule to treat multiple opportunistic viral infections. Sirtuins are NAD+-dependent deacetylases known for their role in life-span increasing effects of caloric restriction and the red wine ingredient, resveratrol. A small molecule screen of Sirtuin modulators has been completed demonstrating effectiveness in inhibiting viral growth in culture. Proposed SBIR Phase I goals are to validate proprietary chemical scaffolds identified in the screen and validate the mechanism of Sirtuin modulation as a host-targeted pan-viral. The focus will be on antiviral activity against CMV, BKV, and JCV, which show cooperativity and commonality across many immunosuppressed conditions beyond transplants, such as HIV infection, and multiple sclerosis, or other conditions by new immunosuppressive therapies. Many of these latter therapies such as rituximab, natalizumab, and efalizumab have been pulled off the market or received black box warnings for reactivation of JC virus leading to progressive multifocal leukoencephalopathy, a rare but fatal inflammation of the brain. Our novel mechanism of action may extend to additional opportunistic viruses to be tested in SBIR Phase II. Minimally, an antiviral against CMV, BKV, and JCV will address unmet medical need for the treatment of these infections, and improve management of immune suppressed patients.